16-176986-C-G

Variant names:

• chr16-176986-C-G
• rs33966883
• NM_000558.5:c.153C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_000558.5(HBA1):​c.153C>G​(p.His51Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H51Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45
• Publications: 3 publications found

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

HBA1 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000294436 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• BP6: Variant 16-176986-C-G is Benign according to our data. Variant chr16-176986-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3766932.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.153C>G	p.His51Gln	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.153C>G	p.His51Gln	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Frankfurt variant (HBA1: c.153C>G; p.His51Gln, also known as His50Gln when numbered from the mature protein, rs33966883, HbVar ID: 73) is reported in the heterozygous state in individuals with normal hematological parameters (see HbVar database and references therein). Additionally, this variant was found in an individual with mild microcytosis, however they also carried the alpha-3.7kb deletion and the p.His51Gln was found on the 3.7kb deletion fusion allele (Prehu 2003). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.562). Based on available information, this variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Prehu C et al. An identical mutation carried by different genes: Hb Frankfurt (alpha50(CE8)His->Gln). Haematologica. 2003 May;88(5):ECR19. PMID: 12745288. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	5.6
DANN	Benign	0.82
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.062	T
PhyloP100		-1.4
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.080	T;T
Vest4		0.48
MutPred		0.93		Loss of catalytic residue at G52 (P = 0.0829);.;
MVP		1.0
ClinPred		0.41	T
GERP RS		-8.6
PromoterAI		-0.019	Neutral
Varity_R		0.52
gMVP		0.69
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs33966883; hg19: chr16-226985;